1. Field of the Invention
This invention relates to radiolabeled proteinaceous substances, methods for making the same, and their use as diagnostic and therapeutic agents.
Radiolabeled compounds are important tools in medical diagnosis and treatment. Such compounds are employed in a variety of techniques, including the diagnosis of deep venous thrombi, the study of lymph node pathology, and the detection, staging, and treatment of neoplasms. A number of these compounds employ metal radionuclides, such as technetium-99m. When employing radionuclides for in vivo administration, it is desirable that the radionuclide localize in a target organ or lesion, e.g., cancer site. Therefore, radionuclides are usually formulated to provide preferential binding to or absorption by the particular organ or tissue. There is considerable interest in being able to accurately direct a radionuclide to a preselected site to reduce background radiation directed to surrounding or distant tissue, reduce the dosage, minimize background for in vivo imaging, and to minimize undesirable side effects. Toward this end, methods involving specific ligands or receptors to which the radionuclide may be conjugated are of interest.
Known radiolabeled compounds and other preparations frequently suffer from one or more distinct disadvantages. For example, in such preparations, the linkage between the radionuclide and the proteinaceous substance of interest may be non-specific and/or unstable, resulting in dissociation of the preparation which, in turn, leads to an increase in background radiation, limits the diagnostic utility of the preparation, and increases the radiation dose to non-targeted sites, limiting the therapeutic efficacy.
Derivatives of proteinaceous substances with protein-chelate conjugates are more stable. However, the preparation of such protein-chelate derivatives may require that the proteinaceous substance be subjected to relatively harsh conditions, e.g., organic solvents and extremes of pH and temperature, which may result in partial denaturation. Additionally, the presence of radionuclide chelates can severely alter the biological activity of particular proteinaceous substances. For example, antibodies covalently labeled with a metal radionuclide via a chelating ligand may be of diminished immunoreactivity which, in turn, diminishes the specificity of their interaction with tissues. Also, proteins subjected to some chelate conjugation methods are prone to denaturation/aggregation; such effects can increase the rates at which such proteins are cleared from the circulation, and therefore decrease the quantity of radionuclide available for imaging or therapy. Furthermore, some proteinaceous substances which are radiolabeled utilizing chelate conjugates may induce an immune response in a patient making any further use of the labeled protein hazardous.
2. Description of the Relevant Literature
References of interest include Steigman, et al., 16 J. Nucl. Med. 573 (1975) (abstract); Pettit, et al., 21 J. Nucl. Med. 59 (1980); and U.S. Pat. Nos. 4,424,200; 4,421,735; 4,323,546; 4,293,537; and 4,057,617.